Human mesenchymal stem cells lose their functional properties after paclitaxel treatment

Abstract

Mesenchymal stem cells (MSCs) are an integral part of the bone marrow niche and aid in the protection, regeneration and proliferation of hematopoietic stem cells after exposure to myelotoxic taxane anti-cancer agents, but the influence of taxane compounds on MSCs themselves remains incompletely understood. Here, we show that bone marrow-derived MSCs are highly sensitive even to low concentrations of the prototypical taxane compound paclitaxel. While MSCs remained metabolically viable, they were strongly impaired regarding both their proliferation and their functional capabilities after exposure to paclitaxel. Paclitaxel treatment resulted in reduced cell migration, delays in cellular adhesion and significant dose-dependent inhibition of the stem cells’ characteristic multi-lineage differentiation potential. Cellular morphology and expression of the defining surface markers remained largely unaltered. Paclitaxel only marginally increased apoptosis in MSCs, but strongly induced premature senescence in these stem cells, thereby explaining the preservation of the metabolic activity of functionally inactivated MSCs. The reported sensitivity of MSC function to paclitaxel treatment may help to explain the severe bone marrow toxicities commonly caused by taxane-based anti-cancer treatments.

The current understanding of mesenchymal stem cells as potential attenuators of chemotherapy‐induced toxicity

“…Analyses reporting the influence of taxanes on MSCs have produced inconsistent results. While paclitaxel treatment was shown to decrease MSC proliferation in a dose‐dependent manner in some publications, other studies showed uniform reduction in cell numbers with no dose‐dependent effects . The MSCs' proliferative ability seems strongly impaired by paclitaxel treatment, although the stem cells remained metabolically viable even after exposure to high doses .…”

“…On a molecular level, up‐regulation of TNF‐α after paclitaxel treatment was found associated with increased apoptosis in MSCs . Additionally, it has been demonstrated that paclitaxel resulted in a significant increase of premature senescence in MSCs, explaining the stem cells' observed preservation of viability despite a strong reduction in proliferation . Contrary to alkylating agents, methotrexate and arsenic trioxide, paclitaxel led to a long‐lasting suppression of cell growth after withdrawal of the drug .…”

“…The MSCs' proliferative ability seems strongly impaired by paclitaxel treatment, although the stem cells remained metabolically viable even after exposure to high doses . The level of apoptosis induction in paclitaxel‐treated MSCs has also been subject to controversy, with several datasets demonstrating slightly or strongly increased apoptosis, while only one publication reported no increase of apoptotic cells . On a molecular level, up‐regulation of TNF‐α after paclitaxel treatment was found associated with increased apoptosis in MSCs .…”

“…While paclitaxel treatment was shown to decrease MSC proliferation in a dose‐dependent manner in some publications, other studies showed uniform reduction in cell numbers with no dose‐dependent effects . The MSCs' proliferative ability seems strongly impaired by paclitaxel treatment, although the stem cells remained metabolically viable even after exposure to high doses . The level of apoptosis induction in paclitaxel‐treated MSCs has also been subject to controversy, with several datasets demonstrating slightly or strongly increased apoptosis, while only one publication reported no increase of apoptotic cells .…”

An Endogenous Anti-aging Factor, Sonic Hedgehog, Suppresses Endometrial Stem Cell Aging through SERPINB2

“…Consistently, oxidative stress-induced expression of these senescence-associated markers was significantly attenuated by SHH treatment (Figures S4A and S4B). As decreased proliferative 28 and migratory 29 capacities are well-known senescence-associated phenotypes in multiple cell types of adult stem cells, we investigated whether SHH alleviates senescence-induced stem cell dysfunctions in vitro. As shown in Figures 1D and 1E, SHH markedly alleviated senescence-induced suppressive effects on the growth and migration of endometrial stem cells.…”